1. Field of the Invention
The present invention relates to the field of reagent dispenser devices and packages, particularly those suitable for repeated introduction of reagents into automated analytical systems.
2. Brief Description of the Prior Art
Reagents are supplied to most analytical systems from separate reagent reservoirs by feed tubing. In many of these systems, the reagents are introduced into a fluid stream in a continuous flow conduit or into a reaction cuvette. The reservoirs are refilled from supply containers in which the reagent is shipped and stored. Some types of reagent storage containers use frangible or breakable capsules or ampules to hold lyophilized or otherwise dried reagent in combination with a reconstituting fluid. This lyophilized form provides the advantage of longterm stability and shelf life in stored reagent.
Some systems have used discrete reaction packages which include reagent sufficient for a single reaction. Sample is introduced and reacts with the reagent therein. Often, the portion of the package in which the reaction occurs is used in the system as an optical cuvette. This type of reaction vessel test pack is disclosed in U.S. Pat. No. Re. 29,725; U.S. Pat. No. 3,986,834; and U.S. Pat. No. 3,036,894. Another example of this type of apparatus is disclosed in U.S. Pat. No. 4,119,407. Certain of these devices provide for filtering capacity whereby reagent and/or sample are filtered prior to their introduction into a reaction chamber. This is disclosed, for example in U.S. Pat. No. 3,437,452.
None of these provides an integral package combining a stable storage/shipment container, reconstituting vessel, reagent reservoir and dispenser which delivers liquid reagent for repeated aspiration of reaction aliquots.
One of the most advanced types of analytical systems is a continuous flow system using conduits whose inner walls are coated with an immiscible liquid, such as the system described in Smythe et al, U.S. Pat. No. 3,479,141, assigned to the instant assignee, which discloses a transport system for automatic analysis apparatus in which a series of aqueous liquid samples are processed as a flowing fluid stream with substantially no contamination between segments. A fluoropolymer conduit and intersample carrier segments of silicone are used. This patent teaches that the silicone encapsulates the aqueous liquid segments, substantially completely eliminating the intermixing of successive liquid segments. Reagents are separately introduced on a continous basis, e.g. in conventional fashion as described with respect to previous continuous flow systems.
In Smythe et al, U.S. Pat. No. 4,253,846, also assigned to the instant assignee, selective injection of reagent into a moving stream of sample segments is provided to such a continuous flow system and allows for an increase in the efficiency and throughput of sample processing. Using injectors such as poppet valves, the reagent is introduced by piercing the immiscible liquid layer encapsulating the selected sample segments. The immiscible liquid layer reforms after injection to maintain sample integrity and prevent carryover. Air and sample are alternately aspirated via a probe which periodically dips into a sample cup. The immiscible liquid is said to be introduced to the inlet end of the probe by an applicator (not shown) and aspirated along with air between successive sample immersions. The immiscible liquid can be a fluorocarbon and both the conduit wall and the poppet valve tip can be a fluorinated polymer. This patent does not further address the actual mechanism of immiscible liquid introduction and clearly indicates that it is separate from the "on-line" introduction of reagent.
Diebler et al, U.S. Pat. No. 4,121,466, also assigned to the instant assignee, disclose a metering apparatus useful to either dispense or aspirate sample. The surface of the aspirating probe is coated with an immiscible liquid film which, in the preferred embodiment, is flowed continuously down the peripheral probe surface at a rate substantially equal to the aspiration rate, so as to be eventually aspirated into the probe inlet. During immersion, excess immiscible liquid on the peripheral probe surface floats onto the surface of the liquid being aspirated but a small film remains on the probe surface. Also, during aspiration, a thin film of immiscible liquid continuously wets the interior probe surface. As the probe is withdrawn, the flow of immiscible liquid is commenced so as to be aspirated along the probe immediately upon withdrawal thereof from the liquid. Segments of the immiscible liquid and aspirated liquid are therefore successively passed along the probe system.
Smythe, U.S. Pat. No. 4,259,291, also assigned to the instant assignee, refers to the continuous flow systems described in the above Smythe et al and Diebler et al patents and addresses the need for more precise and uniform application of protective immiscible liquid coatings. An applicator directly surrounds the probe and layers a thin uniform film of immiscible liquid on the outer surface thereof. The applicator is moved relative to the probe to coat its outer surface. An aspirating mechanism connected to the probe alternately aspirates controlled volumes of air and aqueous sample therethrough. Immiscible liquid is said to be drawn into the probe along with the air segment so aspirated. Thus, alternating sample and air segments encased within the immiscible liquid are passed along the probe to a rotary valve which transfers each aspirated aqueous sample in turn from the probe to a conduit for dispensing to an analytical system. As described herein, a pool of wiped immiscible liquid forms about the probe due to the interplay of surface forces of the liquid in combination with the wetting forces of the immiscible liquid with the respect to the probe surface. When the sample cup is withdrawn from the probe, this pool forms a small globule of immiscible liquid over the inlet of the probe, inasmuch as it preferentially wets the probe material to the substantial exclusion of the aqueous sample. This patent teaches that the globule of immiscible liquid is aspirated into the probe inlet alaong with an air segment. Reagent is introduced "downstream" in a manner which is not further described.
Each of the above patents has provided an advance of one sort or another in the elimination of successive sample intermixing and carryover. This end has been widely recognized as a major consideration in the improvement of continuous flow systems. The combined references provide a significant background literature on the technology available to prevent interaction of segments in continuous flow analysis systems.
Nonetheless, none of these has provided an integral reagent dispenser which is adapted to control the introduction of precise volumes of immiscible liquids to analyzer systems of the continuous flow type. Continuous flow systems using conduits whose inner walls are coated with an immiscible liquid have not been previously available, and thus have not heretofore presented a need such as that addressed by the present invention.